Field of the Invention
This invention is related to a class of synthetic sulfated beta-O4 low molecular weight lignins which are inexpensive to prepare and which have been found to have potent anticoagulation properties in human plasma and whole blood.
Background of the Invention
Heparin (also known as unfractionated heparin (UFH)) is extensively used in the clinic as anticoagulant.1 UFH is obtained from pig intestinal or lung mucosa and is relatively inexpensive. It is then processed to produce low molecular weight heparins (LMWHs), which are also powerful anticoagulants. Enoxaparin is one such LMWH and is obtained from UFH by chemical treatment. Other LMWHs available in the clinic are obtained from UFH either through chemical or enzymatic means.
Both UFH and LMWHs are used to treat numerous thrombotic disorders including deep-vein thrombosis (DVT), disseminated intravascular coagulations (DIC), pulmonary embolism (PE), acute myocardial infarction, unstable angina and cerebrovascular thrombosis.1-3 These are also used during surgery, organ transplantation and for extracorporeal bypass procedures. Combined the annual market of heparins is more than $8 billion within the USA alone.
Yet, both heparins have their own disadvantages. Both agents are heterogeneous mixtures of highly sulfated polysaccharide chains, which introduce a number of issues. The biggest drawback is of significant risk of internal bleeding, which might be of either minor bleed or major bleed type. UFH, and sometimes LMWH, is associated with the occurrence of thrombocytopenia in about 3% of patients.4 Osteoporosis could also arise in some patients upon prolonged heparin usage. In addition to these adverse effects, heparin usage is problematic from quality control and administration perspective. Both UFH and LMWHs possess significant structural variability, which affects their bioavailability and pharmacokinetic parameters. Thus, patient response variability is high. It is also difficult to ascertain the absence of non-heparin-like molecules in a preparation of heparin, e.g., chondroitin sulfate in heparin, because of their structural similarity and mode of preparation. Events of 2008, wherein contamination of UFH by oversulfated chondroitin sulfate led to the death of 81 people in the US, demonstrate the difficulty of quality control with these highly heterogeneous preparations.5 
It would be advantageous to identify new anticoagulants which possess heparin-like activity without the heterogeneity present in UFH and LMWHs. Further, new anticoagulants, particularly which can be obtained through inexpensive route so as to compete with the cost of UFH therapy, will provide useful alternatives for a number of clinical and other applications.